The present invention relates to treating ocular disorders and more particularly to treating glaucoma. U.S. Pat. Nos. 5,798,380, 6,110,912, and 6,586,425, each of which is incorporated herein by reference as if set forth in its entirety, describe in detail the nature and etiology of glaucoma and various therapeutic approaches for reducing intraocular pressure characteristic of the disorder. The incorporated patents disclose methods for enhancing aqueous humor outflow and reducing intraocular pressure in the eye of a subject by administering at least one non-corneotoxic ophthalmic preparation which can comprise at least one macrolide. Additional therapeutic modalities employing other agents are still sought.
Exoenzyme C3 transferase (C3) is an ADP ribosyltransferase that inhibits rho-activated cellular contractility, leading to changes in cell shape and to secondary changes in the actin cytoskeleton and cell adhesion. C3 inactivates Rho by selectively ribosylating Rho proteins on asparagine residue 41. While various activities of exoenzyme C3 are known in general, there is no prior indication of advantageous drainage-enhancing and pressure-reducing activities by C3 in animal eyes. A nucleic acid sequence that encodes C3 from C. botulinum was disclosed by Popoff, M., et al., “DNA Sequence of Exoenzyme C3, an ADP-ribosyltransferase encoded by Clostridium botulinum C and D phages,” N. A. R. 18:1291 (1990) (Genbank Accession Number X51464), incorporated by reference as if set forth herein in its entirety. SEQ ID NO:1 presents the nucleic acid sequence that encodes the C. botulinum C3 exoenzyme; SEQ ID NO:2 presents the encoded amino acid sequence of the C3 enzyme including a short leader sequence at the N-terminus.
Nakamura, Y. et al., “Signaling Mechanism of TGF-Beta1-Induced Collagen Contraction Mediated by Bovine Trabecular Meshwork Cells,” IOVS, mention using C3 to prevent the adverse effects of TGF-Beta1 on the pathophysiology of glaucoma, namely matrix contractility. According to Nakamura et al., TGF-Beta1 induces contractility via activation of Rho and the Ca2+-dependent enzymes PKC and MLCK and that C3 is one way to inhibit the activity of TGF-Beta1. Nakamura et al. make no suggestion that C3 alone can reduce actomyosin contractility, that it can affect outflow facility, or that C3 would be a useful target for treating glaucoma.